Preparing Health Systems for Tumour-Agnostic Treatment

Tumour-agnostic therapies will play an important role in a new era of personalised healthcare, challenging existing diagnostic and value assessment frameworks.

The 2017 A.T. Kearney Foreign Direct Investment Confidence Index: Glass Half Full 1 Advances in oncology have resulted in several revolutionary treatment modalities, which have made inroads into the way we fight cancer. One of these breakthroughs entails the development of medicines that target specific mutations or genomic alterations in different tumours, resulting in a complete and lasting response to treatment in affected patients.1, 2 This new class of treatments is known as “tumour-agnostic” or “histology-independent” therapies because of how they target the genomic alteration within a tumour, regardless of where in the body it has formed.

By the end of 2018, the Food and Drug Administration (FDA) had approved two medicines for tumour-agnostic indications, paving the way for their commercialisation in the US. However, these types of therapies face significant challenges in adoption due to both how these new technologies will be assessed for value and reimbursed, and to the diagnostic infrastructure required to ensure that the patients most likely to respond to these treatments are identified and can gain timely access.

This report was commissioned by F. Hoffmann-La Roche in November 2018 to review the landscape for tumour-agnostic treatment in the five largest European healthcare markets (Germany, France, Italy, United Kingdom and Spain) and Canada. The research is based on a review of publicly available industry reports, articles, recent publications and 30 interviews with oncologists, regulators, health technology assessors, policymakers, pathologists and payers across these markets.

The objective of the landscape review was to better understand the challenges and opportunities faced by tumour-agnostic therapies entering European and Canadian health systems, focusing specifically on the: (a) levels of awareness and prioritisation of tumour agnostics in cancer policy, (b) market entry pathways and approach to value assessment and reimbursement, and (c) readiness of diagnostic infrastructure required for patient identification. These considerations shaped the assessment of countries’ readiness to support access to tumour-agnostic therapies and their availability to patients.

This paper summarises findings from this research and offers an insight into the tumour-agnostic landscape. It provides advice on the topics that stakeholders will need to address to ensure timely patient access to tumour-agnostic treatments. The report is structured as follows:

• A paradigm shift in cancer treatment—presents a background of the tumour-agnostic concept and drug development

• Tumour-agnostic landscape assessment approach—provides a brief overview of the research framework used to assess individual country landscapes

• Key challenges for tumour-agnostic patient access—outlines the key barriers faced by tumour-agnostic treatments in gaining access and reimbursement

• Recommendations for policymakers, regulators, payers and industry—highlights crucial issues for stakeholders to address to ensure tumour-agnostic treatments can be successfully integrated into clinical practice

• Opportunities for multi-stakeholder collaboration—identifies ways in which industry, policymakers, regulators, payers, clinicians and patient representatives can work together to improve patient care in oncology

1 Lasting response is considered greater than six months. 2 Li Yan and Wei Zhang, Precision medicine becomes reality—tumor type-agnostic therapy (Cancer Communications, 2018 38:6)

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 1 A Paradigm Shift in Cancer Treatment

Personalised healthcare is a vital contributor to the future of healthcare provision, with targeted treatments, advanced diagnostics and large-scale analysis of health data providing an unprec- edented opportunity to save or prolong lives and reduce the longer-term cost of care. Cancer is increasingly approached as a genomic disease, with research efforts helping to identify the specific genomic alterations that drive the onset and progression of disease. R&D’s main objective now is to develop new treatments that will target these oncogenic drivers. This in turn has led to significant progress in genomic profiling, next-generation sequencing (NGS) and data analytics—allowing clinicians to recognise the mutations that drive the growth of cancer cells, identify biomarkers and find the patients who are more likely to respond to treatments.

Tumour-agnostic therapies are an important subcategory of personalised medicines and constitute a new era in patient care and drug development. These therapies are distinct from traditional anti-cancer treatments in that they target specific genomic alterations within the tumour, regardless of where in the body the tumour started growing or the tissue it developed from. This constitutes a paradigm shift in how oncology patients are diagnosed and treated, because tumour-agnostic indications have a mutation-specific designation rather than an anatomical or histological one.

As of March 2019, the FDA had approved two tumour-agnostic indications based on the presence of a common biomarker across tumour types. Pembrolizumab was granted accelerated approval for the treatment of patients with unresectable or metastatic, microsatellite instability–high (MSI-H) or mismatch-repair–deficient (dMMR) solid tumours in May 2017, and larotrectinib for solid tumours with neurotrophic receptor tyrosine kinase (NTRK) gene fusion in November 2018.3, 4

These accelerated approvals relied on consultation between manufacturers and the FDA because of the study methodologies used to investigate these small and specific subpopulations. Due to the limited numbers of patients, it was not feasible to study each individual tumour type (from an anatomical point of view) for an individual licencing application and investigators chose to conduct a small number of multi-cohort, single-arm studies, also known as basket trials.5 Pembrolizumab was consequently approved based on five studies in 149 patients across 15 histologies, whereas larotrectinib was studied in three trials including 176 patients across 12 histologies. This represents significantly less data for each tumour type than would usually be expected for tumour type-specific regulatory submissions.

Subsequently, Marketing Authorisation Applications (MAA) for both larotrectinib and entrectinib, two molecules targeting NTRK fusions, have been submitted to the European Medicines Agency (EMA), with pembrolizumab opting not to seek regulatory approval for a tumour-agnostic indication in Europe. A further ~10 tumour-agnostic therapies, targeting the same or various other mutations—including the receptor tyrosine kinases, anaplastic lymphoma kinase (ALK), c-ROS oncogene 1 (ROS1), and rearranged during transfection (RET)—are in early development.6

Tumour-agnostic indications create a new way of thinking about treatment, targeting patients based on a highly specific rare driver mutation (for example, present in less than 1 percent of solid tumours) rather than on tumour type.7 While regulatory agencies are demonstrating

3 Food and Drug Administration, FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication (last updated: 30/05/2017) 4 Food and Drug Administration, FDA approves larotrectinib for solid tumors with NTRK gene fusions (last updated: 17/12/2018) 5 American Society of Clinical Oncology, Clinical Trial design and Methodology (accessed: 25/02/2019) 6 Graber K, Tissue-agnostic cancer drug pipeline grows, despite doubts (Nat Rev Drug Discov. 2018 Apr;17(4):227-229)

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 2 openness to a labelling approach that recognises the histologically independent nature of these therapies and the associated evidence challenges, our research suggests that current approaches to value assessment and the diagnostic infrastructure are not fully adequate for this. As a result, patients’ access to these breakthrough therapies could be adversely impacted.

Decision-makers in oncology are yet to be exposed to the specific challenges these therapies present, such as the small populations in which these mutations may occur within any one tumour type or limited clinical trial data and the need for high-quality diagnostic tests such as broad panel NGS. To ensure effective patient access, these stakeholders will need to be fully aligned on the distinct nature of these therapies, the benefits provided to patients and their broader value to the healthcare system.

Tumour-Agnostic Landscape Assessment Approach

Our review of the tumour-agnostic landscape in the five major EU markets (Germany, France, Italy, UK and Spain) and Canada was conducted through country-level expert interviews and comprehensive secondary research based on an assessment framework, structured around three over-arching access focus areas (see figure 1):

Figure The tumour-agnostic landscape assessment framework is structured around three focus areas

ocus area Enablers

Awareness and • Clinical and scientific community awareness and understanding of tumour-agnostic therapies prioritisation and genomic proiling • Existence and discussion of tumour agnostics in clinical associations, including tissue-specific and rare cancer groups • Importance and availability of guidance to support the launch of speciality therapies • Evolution of guidelines for clinicians in tumour-agnostic therapies and highly innovative or specialty therapies • Existence, awareness and inluence of dedicated patient groups • Active governmental policies supporting highly innovative or specialty therapies • Existence of national or regional cancer plans • Integrated regulatory approval pathways with acceptance of relevant data

HTA, reimbursement • Consideration of tumour-agnostic therapies and genomic proiling by HTA bodies and payers and funding • Adaptive appraisal pathways for tumour-agnostic therapies or other innovative therapies • Evidence sources, endpoint requirements and acceptability of relevant models • HTA value frameworks and elements considered • Reimbursement and funding mechanisms available for innovative drugs

Diagnostic • Existence and sophistication of centres of ecellence and tertiary centres of care infrastructure • Existence of and investment in appropriate diagnostic and data infrastructure • NGS, GS and single-gene testing protocols and reimbursement in place across tumour types

Notes: HTA is health technology assessment. NGS is next-generation sequencing. WGS is whole-genome sequencing. Source: A.T. Kearney analysis

7 Shivaani Kummar, Ulrik N. Lassen. TRK Inhibition: A New Tumor-Agnostic Treatment Strategy (Targeted Oncology, October 2018, Volume 13, Issue 5, pp 545–556)

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 3 • Awareness and prioritisation. We measured the general level of awareness of tumour-agnostic concepts, treatments and patient outcomes among government and regulatory policymakers, the clinical community and various key patient representative forums. Countries’ readiness was further evaluated based on the provisions for tumour-agnostic therapies in national cancer plans, policies and guidelines. For European markets, we also considered the integration of the EMA MAA into fast-track health technology assessments (HTA).

• HTA, reimbursement and funding. We reviewed the fitness of current HTA assessment processes and value frameworks, as well as payer willingness to consider tumour-agnostic medicines as a non-standard case for assessment (for example, making provisions for novel approaches to evidence generation, broader value considerations and innovative funding mechanisms).

• Diagnostics infrastructure. We mapped the local diagnostic infrastructure and assessed government support for, and prioritisation of, high-quality NGS. We also evaluated the development of associated protocols and reimbursement frameworks to support the identification of potential patients for tumour-agnostic treatments.

Although precision medicine is increasingly understood—especially among stakeholders involved with targeted therapies and tumour- specific diagnostics—the general awareness of tumour-agnostic therapies is still relatively low.

Key Challenges for Patient Access to Tumour-Agnostic Treatment

Our review of the country landscapes based on these three focus areas highlighted that no one country system is optimal in enabling access to tumour-agnostic therapies, however best practices, expertise and insights are widely available. We outline five priority enablers which we believe are required to support patient access to tumour-agnostic therapies and provide country- level examples of where policymakers, payers, clinicians and patient representatives have started addressing the challenges. Figure 2 (on page 5) outlines a stepwise approach towards health system readiness across the five enablers, along which countries can be assessed.

Stakeholder awareness of tumour-agnostic therapies A common understanding and endorsement of tumour-agnostic therapies from clinical and patient representatives will be crucial to develop the knowledge base and raise awareness for these therapies. Building this endorsement will be particularly beneficial in countries such as

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 4 Figure A stepwise approach towards health system readiness for tumour-agnostic treatment

Key challenge Tumour-agnostic landscape scenario Stakeholder Clinicians aware of PM Clinicians aware of TA Clinicians have detailed Dedicated clinical awareness of oncology treatments but limited engagement understanding of TA groups established tumour agnostics Low patient group Patient organisations Patient organisations Active and inluential awareness or inluence aware, but little inluence informed and involved patient organisations in HTA

Prioritisation No policy support from Government support Government funding TA seen as a future and government government for NGS and oncology for NGS and oncology policy priority support Requires local regulatory Accepts EMA approval Accepts EMA approval Accepts EMA approval, and HTA process but requires full HTA with ‘fast-track’ HTA fast-track HTA without restriction

HTA acceptance Questions the need Recognition of the need Engaging experts to Adaptive pathway of TA and novel for a tumour-agnostic to create or adapt new create or adapt pathway for TA therapies pathway pathway for PHC or TA for PHC or TA indications assessment data sources

Recognition of the need Consulting experts to Conditional acceptance Acceptance of basket for acceptance of new create new criteria for of safety and eicacy trials and nontraditional trial methodologies trial methodologies with further data methodologies requirements

Reimbursement Temporary or limited Low reimbursement Conditional Full reimbursement and funding for reimbursement potential reimbursement likely mechanisms TA treatments

No special fund for Planning to create a Special oncology funds Special or dedicated oncology treatments special fund for oncology exist at a regional or oncology fund exists treatments provincial level

Maturity of NGS is an exceptional Few diagnostic centres NGS infrastructure exists NGS infrastructure testing landscape practice but scaling and scaling with national coverage

Reimbursement is Reimbursement available Reimbursement budgets Full reimbursement exceptional but limited increasing

Notes: PM is precision medicine. TA is tumour-agnostic. HTA is health technology assessment. NGS is next-generation sequencing. EMA is European Medicines Agency. PHC is personalised healthcare. Source: A.T. Kearney analysis

Italy where there are larger treatment disparities between the north and south, and in Spain where access to tumour-agnostic therapies will require sign-off from 17 autonomous, regional health authorities. In Spain, however, larger health authorities (for example, Andalusia, Catalunya, and Madrid) may conduct pilot projects to provide insights which can be leveraged and ultimately used to raise awareness and inform national-level stakeholders.

This challenge is also actively being addressed in Germany, where the German Society for Haematology and Clinical Oncology (DGHO) is preparing a guideline around an approach to tumour-agnostic treatment; this is due for draft consultation in the second half of 2019. Cancer Research UK (CRUK) is a key member of the UK’s Cancer Taskforce Unit that developed and monitors a 5-year cancer strategy (for 2020), which includes provisions for the rollout of precision medicine. CRUK itself has an active research programme in tumour-agnostic therapies.

However, disparities remain among stakeholder groups around the recognition of tumour- agnostic therapies and their role as a treatment for cancer patients. Although precision

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 5 medicine is increasingly understood—especially among stakeholders involved with targeted therapies and tumour-specific diagnostics (for example, HER2+ in breast cancer, EGFR+ or ALK+ Non-small-cell lung carcinoma)—the general awareness of tumour-agnostic therapies is still relatively low beyond specialist oncologists, researchers and academics. Specialist clinician groups or associations are largely organised around specific tumour types (for example, lung or breast) and focus their discussions on these. And with very small patient populations, tumour- agnostic treatments remain a minor subspecialty within each site-specific group, limiting the potential for endorsement and issuing of related guidance.

Prioritisation and support for precision medicines is still lacking.

The rare incidence of these cancers and cross-cutting nature of tumour-agnostic therapies also poses a challenge to mobilising sufficient patient awareness and influence. Additionally, the nomenclature of tumour-agnostic therapies varies among stakeholders, with a range of different terms used to describe the same concept, including but not limited to “histology independent”, “pan-tumour” and “tissue-agnostic”. These different terminologies may also have slight nuances in definition among stakeholder groups, further complicating understanding. For example, in the context of clinical trials, “pan-tumour” relates to a multi-tumour or basket trial and as such is not limited to trials for treatments with a tumour-agnostic indication.

Prioritisation and government support Governments are generally becoming more aware and supportive of personalised healthcare. This is evident in countries such as France and the UK, which have prioritised the development of NGS infrastructure through clear policy recommendations and targets. However, prioritisation and support for precision medicines is still lacking and most government campaigns remain centred around tumour types.

Although there are no specific provisions for tumour-agnostic therapies, in Canada, an Advisory Panel on Healthcare Innovation has recommended that the government set up an annual $1 billion Healthcare Innovation Fund for new technologies, and the newly-established Canadian Ministry of Innovation is actively investing in infrastructure projects for novel healthcare technologies (including PHC and NGS). In Spain, the current parliament has been working on gaining cross-party approval for a report on the implementation of personalised medicine; this will serve as the baseline for the incoming government to enable personalised medicine as part of a revised national oncology plan.

However, funding arrangements for innovative and personalised medicines are not universally in place, limiting patient access and eligibility for treatment. In some markets where these funding mechanisms are available (for example, through the Cancer Drugs Fund [CDF] in the UK or the acknowledgement of orphan drug designation in Germany), they are coming under increasing scrutiny and may not remain in place for long.8 This emphasises the need for

8 Tumour-agnostics therapies may not qualify as orphan drugs

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 6 governments to prioritise innovation and specifically support personalised healthcare to ensure the ongoing development of novel medicines which optimise treatment efficacy and improve disease management.9

HTA of tumour-agnostic therapies and the use of novel data sources The FDA granted accelerated approvals for the first two tumour-agnostic therapies based on overall response rate (ORR) and response duration, as reported in few patients (149 and 176 patients respectively) across uncontrolled, multicentre, open-label, single-arm clinical trials.10 However, a divergence remains between the approaches taken by regulatory authorities and HTA bodies, both in relation to evidence and definition of outcomes.

The data used by regulators are vastly insufficient for most national HTA bodies, as evidenced by the fact that conditional approvals or approvals under exceptional circumstances by the EMA are negatively correlated to a product’s overall chances of reimbursement.11 In France, for example, the Agence Nationale de Sécurité du Médicament (ANSM) may require the reassessment of evidence provided to the EMA for marketing authorisation, especially for medicines where single-arm or basket trials are concerned.

Dedicated HTA pathways are increasingly being considered for specialised, innovative technologies.

Nevertheless, within the markets reviewed, we have seen a number of relevant developments that could be considered as an approach for the assessment of tumour-agnostic therapies. AIFA (the Italian Medicines Agency) introduced a new algorithm for the assessment of innovative medicines to ensure patients have timely access to lifechanging drugs, which does consider novel (non-RCT) data sources as primary data. The Technical and Scientific committee (CTS) designates medicines as ‘innovative’ based on unmet need, added value and evidence quality with orphan drugs provided a concession from the quality of evidence criterion. Along with consideration of non-RCT data, AIFA’s HTA recommendations will also consider a range of efficacy endpoints beyond overall survival, such as quality of life and clearly measurable biomarkers (for example, size of tumour).12, 13

In the UK, the National Institute for Health and Care Excellence (NICE) has already approved indications for pembrolizumab and atezolizumab based on biomarker tests and has experience in the assessment of medicines using single-arm basket trials. It has also developed a highly specialised technology (HST) pathway, with adjusted thresholds and evidence requirements,

9 Tim Wilsdon, Anthony Barron, et al. The benefits of personalised medicine to patients, society and healthcare systems (July 2018 Report prepared for: European Biopharmaceutical Enterprises (EBE) and the European Federation of Pharmaceutical Industries and Associations (EFPIA)) 10 Li Yan and Wei Zhang, Precision medicine becomes reality—tumor type-agnostic therapy (Cancer Communications, 2018 38:6) 11 Krzysztof Piotr Malinowski, Paweł Kawalec, et al. Reimbursement of Orphan Drugs in Europe in Relation to the Type of Authorization by the European Medicines Agency and the Decision Making Based on Health Technology Assessment (Front Pharmacol. 2018; 9: 1263) 12 Defined by the GRADE (Grading of recommendation, assessment development and evaluation) method 13 Tumour-agnostics therapies may not qualify as orphan drugs

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 7 although the pathway is limited at the moment to single indications in very rare conditions, and it has yet to consider oncology drugs. Each of these examples shows that dedicated HTA pathways are increasingly being considered for highly specialised or innovative technologies and could be a platform or model for assessing tumour-agnostic therapies.

However, compared to regulatory agencies, HTA processes in most countries place a heavy weight on certain data types, highlighting three limitations in tumour-agnostic therapy data collection:

—— Trial design. There is a lack of recognition for novel trial designs, such as basket trials which are crucial for the development of treatments for rare mutations; instead, HTA entities strongly favour randomised control trials with straightforward designs.

—— Evidence versus an active comparator. HTA agencies tend to request the active comparator(s) that are most relevant to their country (for example, the “standard of care”), but tumours may have different (or non-existing) current standards of care depending on site.

—— Biomarker-based endpoints. A lack of certainty or acknowledgement of their link to overall survival may result in biomarker-based endpoints being considered as secondary or tertiary outcomes in assessment, thus devaluing the level of evidence presented to an HTA panel.

Additionally, HTA bodies may require the full cost of NGS to be covered within a tumour-agnostic submission dossier, making the demonstration of value even more challenging since the healthcare system benefits of NGS are not directly attributed to the submission in question. However, this does provide an opportunity for industry collaboration in the funding for treatment-relevant, high-quality NGS.

Taken together, these factors and the difference in weighting of value dimensions by national bodies result in inconsistencies in the types of evidence required, reimbursement recommendations and ultimately pricing decisions. It is unlikely that the HTA systems in the countries studied will recommend the use and reimbursement of tumour agnostics through a standard HTA without qualification.

Reimbursement and funding for tumour-agnostic treatments Many of the countries reviewed assess the value or level of innovation relative to current standards of care. Tumour-agnostic therapies will cover multiple standards of care and comparators, and in some cases it is simply not clinically feasible or economically effective to collect robust comparative clinical data, thus increasing the complexity in defining a representative consistent or universal value for a payor across all the applications of the therapy.

In 2011, the UK established the Cancer Drugs Fund (CDF) and adjusted it in 2016 to provide dedicated access to promising new treatments via managed entry arrangements (MEAs), stipulating ongoing evidence collection to address clinical uncertainty.14 Currently, this fund is limited to £340 million per year, and focuses on funding cancer treatment awaiting full NICE assessment.

In Italy, uncertainty in clinical evidence is routinely addressed through MEAs, with AIFA overseeing the most advanced schemes in Europe; these are enabled by pioneering, oncology- focused national healthcare registries, which are well suited to support the evidence generation

14 NHS England, Cancer Drugs Fund, (accessed: 25/02/2019)

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 8 required. In addition to this, innovative oncology medicines (as designated by the CTS) gain access to dedicated funding of about €500 million per year.15 Although innovation funding is a step in the right direction, there is limited clarity on how such funding can be allocated to support patient access to tumour-agnostic therapies, as eligibility criteria do not consider the limited data and the pan-tumour nature of therapies.

Several of the challenges we found with current HTA approaches are likely to also be reflected in pricing and reimbursement. Given the limited evidence base at launch, ongoing evidence collection is essential to build up safety and efficacy profiles in eligible populations. Most countries reviewed currently address this uncertainty through relatively simple non-disclosed, discount-based managed entry agreements. However, these types of agreements may neither address this uncertainty nor provide the incentive for ongoing data collection.16

Tumour-agnostic therapies will require more flexible commercial arrangements.

With this in mind, we believe that tumour-agnostic therapies will require more flexible commercial arrangements to allow for appropriate value recognition and ensure that payers reimburse products on the basis of value delivered.

A suitable testing landscape Current diagnostic techniques such as immunohistochemistry (IHC) focus on testing a limited number of tumours and increasingly face constrained capacity and a lack of funding for expansion. Developing a suitable landscape for tumour agnostic therapies will require the advancement in physical infrastructure, diagnostic protocols and reimbursement frameworks for high-quality NGS.

We have found a number of best practice examples of NGS capability development covering both policy direction and infrastructure development. The French government has committed to rolling out NGS, with the Ministry of Health providing funding for all diagnostics tests capped at about €380 million and around 12 percent of addressable cancer patients receiving NGS testing. Germany is currently establishing several new NGS centres of excellence (for example, West German Genome Centre and in Tübingen, Dresden and Kiel), which experts believe will be operational in the latter half of 2020; however, reimbursement is very limited and only available in selected areas. In Canada, NGS is currently available through academic medical centres in the more populated areas of British Columbia, Ontario and Quebec, but is only reimbursed in British Columbia and Ontario.

Although in most countries in this review there is national-level acknowledgment of the need to roll out high-quality NGS and invest in infrastructure, plans to develop the necessary capabilities and protocols are not yet in place. Key elements, such as agreement on broad panel testing,

15 Mapi, AIFA releases new requirements for innovative products (Real World Strategy & Analytics Blog, accessed: 25/02/2019) 16 Panos Kanavos, Alessandra Ferrario, et al. Managing Risk and Uncertainty in Health Technology Introduction: The Role of Managed Entry Agreements (Global Policy Volume 8. Supplement 2. March 2017)

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 9 bioinformatic analysis and reimbursement, all require prioritisation and significant focus. This will be especially important for rarer mutations such as NTRK gene fusions, which will rely more heavily on sequencing expertise and efficient protocols due to their exceptional rarity.

Preparing Health Systems

Not only do tumour-agnostic therapies promise significant improvements in clinical outcomes, they also considerably advance our understanding of mutation-specific and biomarker-driven approaches to cancer diagnosis and treatment. However, as this landscape review has shown, the adoption of tumour-agnostic therapies presents a number of challenges inherent to their nature and how they have been developed.

To realise the benefits of these new therapies and facilitate patient access to tumour-agnostic therapies, policymakers, regulators, payers and industry will need to take several actions to ensure uptake and encourage ongoing innovation in the relevant cancers.

• Create alignment between regulators and HTA bodies. Regulators and national HTA organisations should come together to align on principles that support innovation and accelerate patient access by expediting the development and review of therapies, allowing approval and reimbursement based on proven surrogate endpoints and unmet medical needs.

Current accelerated approvals and ‘fast track’ designations are designed to promote patient access to innovative and lifesaving treatments, but as regulatory agencies begin to accept biomarker-driven indications, other pathways (for example, HTA processes) will need to align. For example, rare mutations are not eligible for orphan drug designations. Even where prevalence is sufficiently low (for example, <5 in 10,000), their potential to address multiple (or tumour-agnostic) indications limits a treatment’s ability to be granted the HTA data requirement concessions offered to drugs awarded orphan status.

Multi-stakeholder partnerships to develop common guidance and methodologies for tumour- agnostic therapies can benefit regulators, HTA bodies and manufacturers. EUnetHTA aims to consolidate some aspects of HTA assessments (within the EU) and can be leveraged as an initial point for cross-country and agency collaboration.

This will also enable the cross-border sharing of therapy area and assessment expertise, especially in rare and specialist treatments. Early consensus and endorsement of research methodologies and data collection requirements will help to focus product development and data collection, whilst international expertise will empower local HTA agencies by improving consistency and speed of assessments.

• Adaptive HTA processes. HTA pathways for precision oncology need to allow for the appropriate assessment of tumour-agnostic therapies without tumour type-specific licences or RCT data. While some markets may already have dedicated HTA pathways, often they are not fit for purpose.

Those designing an adaptive pathway will need to consider the limitations of tumour-agnostic data generation and trial design by providing allowances for surrogate or biomarker-based endpoints and basket trials. It will also be important to recognise the site-independent nature of responses to therapies, thus accounting for multiple comparators within a single indication. Lastly, infrastructure will be required to facilitate ongoing data collection to monitor drug development and inform further evaluations. Adaptive HTA pathways will benefit from collaboration with regulatory bodies, leading to an integrated approach to share

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 10 expertise and provide more consistent recommendations based on common data and value elements, thereby avoiding delays in patient access.

• Evolve managed entry agreements (MEAs) beyond discounts. As treatments become more personalised, innovative reimbursement models and more reactive market entry agreements (for example, outcomes-based payment or risk sharing) have a key role to play in enabling pricing and reimbursement, and therefore patient access. These agreements will need to be flexible enough to assess value by considering the limitations of evidence at launch, small patient populations, multiple comparators and actual clinical practice.

MEAs can facilitate greater patient access whilst sharing the financial risk and incentivising data collection. Italy has engaged in wide-scale implementation of MEAs since nationwide, web-based product registries were developed in 2006. These MEAs include risk-sharing, payment by results and success fee agreements, based on observed patient outcomes. It has resulted in faster patient access and better value recognition. The burden of administrating this infrastructure is shared by manufacturers, with pharmaceutical companies paying a yearly €30,000 fee for each registry that includes its products.17

MEAs can act as a bridge between price and value, as assessed by HTA authorities, easing pressures on authorities to ensure earlier access and reducing the risks associated with new therapeutic mechanisms. Specifically, within tumour-agnostic therapies, gaining multi- stakeholder input and designing fit-for-purpose commercial agreements can ensure payers pay only for the outcomes delivered, irrespective of which tumour type the product is used in. They also simultaneously facilitate the ongoing data capture required to validate safety and efficacy.

• Invest in high-quality NGS capabilities and protocols. NGS technology has improved significantly over recent years in terms of reliability, analysis, interpretation and cost, increasing the feasibility of its use in everyday clinical practice. National cancer plans should lay out clear road maps for NGS capability building and funding, along with protocols to facilitate uptake and appropriate use. It is important that these protocols extend beyond the more common cancers (for example, non-small-cell lung carcinoma, where they are currently mostly used) and support the use of high-quality NGS for all tumour types. Consideration should also be given to novel or special reimbursement mechanisms to support sequencing for innovative medicines to ensure the inclusion of rare and orphan drug patients.

The use of NGS has become common within cancer research and many research centres offer this service to clinicians. However, its routine use beyond the United States, where Medicare began covering tests in advanced cancer patients in March 2018, is still limited.18 Per its Genomic Medicine Plan 2025, France aims to become one of the leading countries in personalised and precision medicine by integrating genomic medicine into the care pathway and providing access for all patients with cancer and rare diseases by 2025.19

High-quality NGS is a breakthrough technology that can increase diagnostic throughput, provide greater accuracy and enable bioinformatics. With commitment from policymakers and payers to build capacity and ensure adequate reimbursement and funding, it will not only greatly benefit patients, but will enable significant efficiencies and savings across healthcare systems, whilst being an essential part of advanced cancer care delivery.

17 Towse, A., Cole, A., and Zamora, B. The Debate on Indication-Based Pricing in the U.S. and Five Major European Countries (Office of Health Economics, Consulting report, May 2018) 18 iSpecimen, Medicare to cover next-generation sequencing for cancer patients (published online 30/03/2018) 19 Aviesan. Genomic medicine France 2025 (https://solidarites-sante.gouv.fr/IMG/pdf/genomic_medicine_france_2025.pdf, accessed 25/02/2019)

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 11 • Improve the health data landscape. Many new therapies are likely to achieve regulatory approval with a limited data set, either because of accelerated approval timelines, or because fully powered studies are impractical or cost-prohibitive. Post-approval evidence collection will therefore be required to understand how these new medicines perform in real clinical settings. A coordinated approach to registry development is likely to be required especially considering the small populations covered and the pan-tumour nature of the technologies.

Since 2006, Italy has had access to nationwide web-based registries for each product indication or line of treatment, routinely collecting information on patient eligibility, medicines supply, dispensing and follow-up. Although this model could be scaled and imple- mented across countries, key challenges such as incentives for prescribers to undertake the required administration and centralised management will need to be addressed. Improving the health data landscape will require joint action by patients, policymakers and private entities working together at an international level and managing one data set that can be analysed to the benefit of all stakeholders. This includes raising awareness of the benefits of health data, fostering alignment across data policies, and developing consistent standards and skills supported by the necessary infrastructure.20

Ultimately, such an approach will provide scalable data sets that will allow stakeholders to study treatment effects in even the smallest tumour-agnostic populations and provide a platform for regulatory and HTA agencies to review products on an ongoing basis. It will also facilitate the implementation of outcomes-based MEAs and real-world validation of clinical trial results.

Opportunities for Multi-Stakeholder Collaboration

Today, more people than ever before are being diagnosed with cancer and physicians are increasingly focused on specific tumour types. This tumour-specific paradigm of cancer treatment is often reinforced by governments, HTA agencies, and patient and charitable organisations that centre their work around site-specific cancer populations, thus highlighting the heterogeneity between tumour types. Tumour-agnostic therapies will therefore require a profound change in how we think about cancer if we are to realise the promise of personalised medicine.

As it is, we are already building our understanding of cancer as a genomic disease: precision oncology has entered mainstream clinical practice, with clinicians increasingly using molecular profiling to identify targetable alterations and tailor treatments to their patients.21 Ensuring tumour-agnostic therapies are available to oncology patients despite the identified challenges will also require both national- and international-level collaboration from policy, government, payer, clinical, patient and industry stakeholders.

The first step will require the involvement of key stakeholder groups—notably, regulators, national HTA bodies, clinicians, patients’ representatives and manufacturers—to consider the barriers and potential solutions laid out in this review and agree on a road map for change. Initiatives such as the German government’s ‘pharma dialogue’ can act as a blueprint for such discussions on tumour-agnostic treatments, at both a national level and pan-national level.

20 European Federation of Pharmaceutical Industries and Associations. EFPIA Report on oncology health data in Europe (https://www.efpia.eu/media/412128/efpia-oncology-data-report.pdf, accessed 25/02/2019) 21 Schwartzberg L, Kim ES, et al. Precision Oncology: Who, How, What, When, and When Not? (Am Soc Clin Oncol Educ Book. 2017;37:160-169)

Report on the Readiness of Health Systems for the Introduction of Tumour-Agnostic Treatment 12 A second step will include the sharing of expertise and capabilities from both the public and private sectors to identify best practices and develop pilot initiatives with feasible action plans. In Spain, for example, industry stakeholders have been working with local healthcare providers to jointly fund two immunochemistry diagnostics centres for lung cancer patients. Such local initiatives can serve as a model for the changes that are required on a health system level.

Only through the collaboration of informed stakeholders with patients at the forefront of their minds can solutions be developed to ensure the ongoing development of and access to innovative, sustainable care for patients.

Acknowledgements

This report was commissioned and funded by F. Hoffmann-La Roche. It was authored by Michael Thomas (partner, A.T. Kearney), Darshan Vora (principal, A.T. Kearney) and Handre Schmidt (manager, A.T. Kearney). The authors would like to thank Calypso Montouchet, Jure Kocman and Chris Williams for their contributions to the research and drafting of this report. We are also grateful to the interviewees who participated in this assessment via interviews conducted from December 2018 to January 2019.

Authors

Michael Thomas, partner, London Darshan Vora, principal, London [email protected] [email protected]

Handre Schmidt, consultant, London [email protected]

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